PROJECT SUMMARY/ABSTRACT?Neurobiology and Brain Tumor Program Brain tumors are the leading cause of cancer-related death in children. Despite rapid advances in our understanding of disease biology, current treatment approaches are still lacking for some patients and lead to long-term, debilitating side effects in others. The goal of the Neurobiology and Brain Tumor Program (NBTP) is to improve survival and morbidity for children with brain tumors by developing effective, relatively non-toxic therapies through a better understanding of disease pathogenesis. The NBTP is an established multidisciplinary Program with a proven record in translating fundamental neuroscience and cancer biology discoveries into novel diagnostics and clinical trials. Our genome-wide studies of the major pediatric brain tumor types identified novel mutations, defined molecular subgroups, and opened new avenues of basic, translational, and clinical investigation. Exciting advances in the fields of molecular pathology, imaging, and radiation oncology provide additional promise for progress in treatment of these clinically formidable diseases. Drs. Suzanne Baker (laboratory lead), an expert in the molecular pathogenesis of brain tumors and Amar Gajjar (clinical lead), a nationally recognized leader in pediatric brain tumor therapeutics are responsible for the leadership of the Program. To facilitate collaboration and drive translation, the NBTP is organized into 3 working groups: Fundamental Neurobiology, Translational Research, and Brain Tumor Therapy. The NBTP has 16 Full Members and 3 Associate (junior mentored) Members, representing the Departments of Bone Marrow Transplantation and Cellular Therapy, Cell and Molecular Biology, Developmental Neurobiology, Genetics, Oncology, Pathology, Pediatric Medicine, Pharmaceutical Sciences, and Radiation Oncology. Program members have a total of $3.8M in annual peer-reviewed funding, including $2.6M in NCI funding, Research from the NBTP has resulted in 458 publications, of which 31.4% are intra-programmatic, 29.9% are inter- programmatic, and 77.5% are inter-institutional (with other NCI-designated Cancer Centers). In addition, during the funding period (2013-2017) the NBTP contributed 879 interventional enrollments of which 762 were therapeutic enrollments. During the current funding period, NBTP accomplishments led to a paradigm shift in the global understanding and treatment of commonly diagnosed pediatric brain tumors. Results from key NBTP studies included an unprecedented view of the somatic mutation landscape of several pediatric brain tumors; novel oncogenic drivers of DIPG and ependymoma; discovery of extensive heterogeneity within virtually all pediatric brain tumor histotypes; and new insights into the cellular origins and pathogenesis of pediatric brain tumors. NBTP members also translated our fundamental genetic discoveries into 4 early-phase clinical trials (SJHG12, SJPDGF, SJDAWN, SJATRT) and the precision medicine phase II trial SJMB12, a randomized, multicenter international study for newly diagnosed medulloblastoma. SJMB12 is the first trial in North America to assign strata based on molecular classification, with therapy translated from NBTP preclinical studies.